SINK COVID-19: Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19

• Sponsor: William Beaumont Hospitals (Other)
• Overall Status: Terminated
• CT.gov ID: NCT04365985
• Collaborator: (none)
• Enrollment: 70
• Location: 1
• Arms: 3
• Actual Duration (Months): 11.1
• Patients Per Site Per Month: 6.3

Study Details

Study Description

Brief Summary

Ideal new treatments for Novel Coronavirus-19 (COVID-19) would help halt the progression disease in patients with mild disease prior to the need for artificial respiration (ventilators), and also provide a rescue treatment for patients with severe disease, while also being affordable and available in quantities sufficient to treat large numbers of infected people. Low doses of Naltrexone, a drug approved for treating alcoholism and opiate addiction, as well as Ketamine, a drug approved as an anesthetic, may be able to interrupt the inflammation that causes the worst COVID-19 symptoms and prove an effective new treatment. This study will investigate their effectiveness in a randomized, blinded trial versus standard treatment plus placebo.

Condition or Disease	Intervention/Treatment	Phase
COVID-19; Acute Respiratory Distress Syndrome; Severe Acute Respiratory Syndrome (SARS); Coronavirus Infections	Drug: Naltrexone; Drug: Ketamine; Other: Placebo	Phase 2

Detailed Description

There is an urgent need to develop new treatments for Novel Coronavirus-19 (COVID-19) infection using easily available and affordable medications. We need to develop a treatment protocol which prevents progression of the disease and a treatment protocol to rescue those with advanced disease. In addition to anti-viral therapeutics currently under investigation in other trials, the addition of immunomodulators to the treatment regimen appears have to potential to act as agents which can reduce the pathogenicity of this disease by reducing the dysregulation of autoimmunity which is destructive of normal tissue and when unchecked rapidly leads to mortality.

COVID-19 infection has three stages and 80% of infected people stay in stage 1 or stage 2A (viral response and early pulmonary effects), however 20% of patients progress to stage 2B (late pulmonary effects), and of those about 20% progress to stage 3 (hyper-inflammation). An ideal treatment for COVID-19 would have a two-pronged strategy: a treatment that would slow or interrupt the progression of the disease from mild/moderate (stage 1-2A) to severe (stage 2B-3), and a treatment to rescue patients who have become severe. Promising data using tocilizumab, an monoclonal antibody targeting the cytokine Interleukin-6 (IL-6), suggests that interrupting IL-6 is one of the potential pathways to accomplish this.

Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia and other pain conditions. Lower than standard doses of naltrexone inhibit cellular proliferation of T- and B- cells and block Toll-like receptor 4 (TLR4), providing pain relief and anti-inflammatory benefit. Naltrexone at doses below the normal therapeutic dose appears to reduce production of multiple cytokines including IL-6 in a steady pace and is available as an oral preparation. As such it is ideal to use to attempt to modify progression to stage 2B as it can easily be given to both hospitalized patients and patients in the community.

Ketamine at low doses, below the normal anesthetic dose, appears to rapidly reduce the production of pro-inflammatory cytokines, especially IL-6 and tumor necrosis factor alpha (TNFα), for hours after an event which would induce the inflammatory response. This drug is given intravenously (IV), either by drip or push, and is easily given in a hospital environment. This could not easily be used in the community but could act as a rescue drug with lower cost and easier availability than tocilizumab, a monoclonal antibody targeting IL-6. Ketamine has been extensively studied in a variety of settings and indications with a well-established side-effect and dosing profile. Ketamine is generally well tolerated and remains inexpensive and widely available on the U.S. market and available for immediate use.

The trial will measure the ability of low dose naltrexone to reduce the progression of participants with COVID-19. In this study, naltrexone or placebo will be given to participants in early stages of COVID-19 infection in a randomized, double blinded manner, whereas the use of ketamine will be unblinded and given as a rescue agent should a participant progress. Additionally, should a participant be ineligible for the randomized portion of the study due to already being in a more advanced stage of the disease, they will be given the opportunity to enter the trial to receive ketamine without being randomized to naltrexone vs placebo.

Participants will continue to receive any standard of care COVID-19 treatment during their participation in this study. Laboratory blood tests such as IL-6 concentration, blood counts, liver and renal function panels as well as close physician supervision will be used to monitor participant condition during hospitalization. Participants will be contacted 1 month post discharge to evaluate outcomes and potential side effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Intervention Model Description: Prospective, single center, randomized, double blinded study of naltrexone with an open label extension using ketamine as a rescue drug for patients who progress in their diseaseProspective, single center, randomized, double blinded study of naltrexone with an open label extension using ketamine as a rescue drug for patients who progress in their disease
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: No other parties blinded
• Primary Purpose: Treatment
• Official Title: Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19
• Actual Study Start Date: Apr 29, 2020
• Actual Primary Completion Date: Apr 1, 2021
• Actual Study Completion Date: Apr 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19	Other: Placebo; Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.; Other Names: sugar pill
Experimental: Naltrexone Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19.	Drug: Naltrexone; Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..; Other Names: ReVia Vivitrol
Experimental: Ketamine Ketamine IV infusion (0.15 mg/kg based on total body weight for maximum 20 mg every 6 hours) for patients with stage 2B or stage 3 COVID-19; may be increased to 0.3 mg/kg based on total body weight for a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well.	Drug: Naltrexone; Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..; Other Names: ReVia Vivitrol ; Drug: Ketamine; Low dose ketamine hydrochloride given intravenously at a dosage of 0.15 mg/kg body weight for maximum 20 mg every 6 hours, to inpatient participants with advanced oxygenation requirements from either time of admission or time of progression of mild/moderate disease until time participant is stable for discharge, as a rescue treatment. If patient is transferred from the naltrexone or placebo arm, they will continue to receive naltrexone/placebo. Dosage of ketamine may be increased to 0.3 mg/kg body weight, maximum 30 mg every 6 hours, if participant does not respond at the lower dosage. Ketamine can be reduced back to 0.15 mg/kg at the clinical decision of the investigator and when patient has hypertensive emergency, the dose can be held until hypertensive emergency is controlled.; Other Names: Ketalar ; Other: Placebo; Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.; Other Names: sugar pill

Outcome Measures

Primary Outcome Measures

1. Progression of Oxygenation Needs [up to 1 month]

   Count of participants initially presenting with mild/moderate disease who progress to requiring advanced oxygenation (high flow nasal canula, non-rebreather, continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), or intubation)

Secondary Outcome Measures

1. Renal Failure [up to 1 month]

   Count of participants who develop or experience worsened renal failure as defined by RIFLE criteria, a 5-point scale where the categories are labeled: Risk-Injury-Failure-Loss-End stage renal disease, with Risk being the least severe and End stage renal disease being the most severe. The criteria for determination of stage are factors of serum creatinine and urine output. Numbers of participants worsening one or more RIFLE stages will be reported.

2. Liver Failure [up to 1 month]

   Count of participants who develop or experience worsened liver failure as defined by serum transaminases five times normal limits

3. Cytokine Storm [up to 1 month]

   Count of participants who develop cytokine storm as measured by elevated markers of inflammation (elevated D-dimer, hypofibrinogenemia, hyperferritinemia), evidence of acute respiratory distress syndrome (ARDS) measured by imaging findings and mechanical ventilator requirements, and/or continuous fever (≥ 38.1 ° Celsius unremitting)

4. COVID Mortality [up to 1 month post hospital discharge]

   Count of participants who die from COVID-19

5. Length of Hospital Stay [up to 1 month]

   Length of hospital stay in days

6. Intensive Care Unit (ICU) Admission [up to 1 month]

   Count of patients admitted to the ICU at any time during index hospitalization

7. Intensive Care Unit (ICU) Duration [up to 1 month]

   Length of ICU stay in days

8. Intubation [up to 1 month]

   Count of participants requiring intubation

9. Intubation Duration [up to 1 month]

   Length of intubation, measured in days

10. Time Until Recovery [up to 1 month]

    Time measured in days from hospital admission to determination patient is stable for discharge

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Positive for COVID -19

• Admitted to Beaumont Hospital - Royal Oak, Michigan

• Age ≥18

• Receiving ≤ 6 liters/minute oxygen by nasal cannula for randomization to either placebo or naloxone arm OR receiving ≥ 6 liters/minute oxygen by nasal cannula or requiring advanced oxygenation for placement in ketamine arm

Exclusion Criteria:

• Known allergy to naltrexone

• Known allergy to ketamine

• Diagnosis of schizophrenia or psychosis

• Pregnancy based on available medical history, existing labs, or verbal report

• On chronic high dose opioids > 90mg morphine mg equivalence

• Use of naltrexone or Vivitrol within 90 days

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	William Beaumont Hospital	Royal Oak	Michigan	United States	48073

Sponsors and Collaborators

• William Beaumont Hospitals

Investigators

• Principal Investigator: Matthew Sims, MD PhD, Beaumont Health

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 2, 2021

More Information

Publications

None provided.

• Responsible Party: Matthew Sims, MD, PhD, Director Infectious Disease Research, Beaumont Health; Professor of Internal Medicine and Foundational Medical Studies, OUWB School of Medicine, William Beaumont Hospitals
• ClinicalTrials.gov Identifier: NCT04365985
• Other Study ID Numbers: 2020-097
• First Posted: Apr 28, 2020
• Last Update Posted: Jan 26, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Matthew Sims, MD, PhD, Director Infectious Disease Research, Beaumont Health; Professor of Internal Medicine and Foundational Medical Studies, OUWB School of Medicine, William Beaumont Hospitals: naltrexone; ketamine; cytokine storm; Interleukin-2; therapeutic treatment
• Additional relevant MeSH terms: COVID-19; Coronavirus Infections; Severe Acute Respiratory Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome; Naltrexone; Ketamine

Study Results

Participant Flow

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Period Title: Overall Study
STARTED	9	9	52
COMPLETED	9	9	52
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Naltrexone	Ketamine	Total
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Total of all reporting groups
Overall Participants	9	9	52	70
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.45 (16.29)	68.52 (10.00)	68.11 (13.20)	67.82 (13.12)
Sex: Female, Male (Count of Participants)
Female	4 44.4%	4 44.4%	18 34.6%	26 37.1%
Male	5 55.6%	5 55.6%	34 65.4%	44 62.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	2 3.8%	2 2.9%
Not Hispanic or Latino	8 88.9%	8 88.9%	44 84.6%	60 85.7%
Unknown or Not Reported	1 11.1%	1 11.1%	6 11.5%	8 11.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	3 33.3%	1 11.1%	10 19.2%	14 20%
White	6 66.7%	7 77.8%	32 61.5%	45 64.3%
More than one race	0 0%	0 0%	8 15.4%	8 11.4%
Unknown or Not Reported	0 0%	1 11.1%	2 3.8%	3 4.3%
Region of Enrollment (participants) [Number]
United States	9 100%	9 100%	52 100%	70 100%

Outcome Measures

1. Primary Outcome

Title	Progression of Oxygenation Needs
Description	Count of participants initially presenting with mild/moderate disease who progress to requiring advanced oxygenation (high flow nasal canula, non-rebreather, continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), or intubation)
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	9	9	52
Count of Participants [Participants]	1 11.1%	0 0%	21 40.4%

2. Secondary Outcome

Title	Renal Failure
Description	Count of participants who develop or experience worsened renal failure as defined by RIFLE criteria, a 5-point scale where the categories are labeled: Risk-Injury-Failure-Loss-End stage renal disease, with Risk being the least severe and End stage renal disease being the most severe. The criteria for determination of stage are factors of serum creatinine and urine output. Numbers of participants worsening one or more RIFLE stages will be reported.
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

Missing data for 4 patients in Ketamine group

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	9	9	48
Count of Participants [Participants]	1 11.1%	0 0%	12 23.1%

3. Secondary Outcome

Title	Liver Failure
Description	Count of participants who develop or experience worsened liver failure as defined by serum transaminases five times normal limits
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

Missing data for 4 patients in Ketamine group

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	9	9	48
Count of Participants [Participants]	0 0%	0 0%	4 7.7%

4. Secondary Outcome

Title	Cytokine Storm
Description	Count of participants who develop cytokine storm as measured by elevated markers of inflammation (elevated D-dimer, hypofibrinogenemia, hyperferritinemia), evidence of acute respiratory distress syndrome (ARDS) measured by imaging findings and mechanical ventilator requirements, and/or continuous fever (≥ 38.1 ° Celsius unremitting)
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

Missing data for 4 patients in Ketamine group

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	9	9	48
Count of Participants [Participants]	0 0%	0 0%	0 0%

5. Secondary Outcome

Title	COVID Mortality
Description	Count of participants who die from COVID-19
Time Frame	up to 1 month post hospital discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	9	9	52
Count of Participants [Participants]	0 0%	0 0%	16 30.8%

6. Secondary Outcome

Title	Length of Hospital Stay
Description	Length of hospital stay in days
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

Admission data not collected for Placebo and Naltrexone patients. Missing discharge data for 5 patients in ketamine group.

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	0	0	47
Mean (Standard Deviation) [days]	21.37 (15.89)

7. Secondary Outcome

Title	Intensive Care Unit (ICU) Admission
Description	Count of patients admitted to the ICU at any time during index hospitalization
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

Data not available for 1 patient in Naltrexone group and 5 patients in Ketamine group

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	9	8	47
Count of Participants [Participants]	2 22.2%	1 11.1%	28 53.8%

8. Secondary Outcome

Title	Intensive Care Unit (ICU) Duration
Description	Length of ICU stay in days
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

Patient in naltrexone group admitted to ICU had length of stay=0

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	2	1	28
Mean (Standard Deviation) [days]	2.56 (0.71)	0 (0)	16.68 (11.25)

9. Secondary Outcome

Title	Intubation
Description	Count of participants requiring intubation
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	9	9	52
Count of Participants [Participants]	0 0%	1 11.1%	29 55.8%

10. Secondary Outcome

Title	Intubation Duration
Description	Length of intubation, measured in days
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

No patients in Placebo group were intubated. For those intubated, data not available for 4 patients of 29 intubated in the Ketamine group

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	0	1	25
Mean (Standard Deviation) [days]	3.32 (0)	15.53 (14.12)

11. Secondary Outcome

Title	Time Until Recovery
Description	Time measured in days from hospital admission to determination patient is stable for discharge
Time Frame	up to 1 month

Outcome Measure Data

Analysis Population Description

Patients not included who died during admission. Of 28 patients in ketamine group surviving to discharge, data missing for 5 patients. Of 8 patients in naltrexone group surviving to discharge, data missing for 1 patient.

Arm/Group Title	Placebo	Naltrexone	Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.	Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..	Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
Measure Participants	9	7	23
Mean (Standard Deviation) [days]	8.67 (5.79)	8.71 (7.91)	17.57 (22.14)

Adverse Events

Time Frame	1 month
Adverse Event Reporting Description	Systematic assessment of adverse events by review of medical records
Arm/Group Title	Placebo		Naltrexone		Ketamine
Arm/Group Description	Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.		Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..		Ketamine IV infusion (0.15 mg/kg maximum 20 mg every 6 hours) for patients with stage 2B or 3 COVID-19; may be increased to 0.3 mg/kg to a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well. Naltrexone: Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatients with mild/moderate COVID-19. Naltrexone will continue for 1 month post discharge. Patients progressing to requirement for advanced oxygenation will be reassessed and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation . Placebo: Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
All Cause Mortality
	Placebo		Naltrexone		Ketamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		1/9 (11.1%)		24/52 (46.2%)
Serious Adverse Events
	Placebo		Naltrexone		Ketamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/9 (44.4%)		9/9 (100%)		52/52 (100%)
Blood and lymphatic system disorders
ACUTE ANEMIA	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
ANEMIA	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
ANEMIA REQUIRING TRANSFUSION	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
HEMORRHAGE	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
HEMORRHAGIC SHOCK	0/9 (0%)	0	0/9 (0%)	0	3/52 (5.8%)	3
HYPERKALEMIA	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
HYPOTENSION	0/9 (0%)	0	0/9 (0%)	0	5/52 (9.6%)	5
LABILE HYPOTENSION	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
SHOCK	0/9 (0%)	0	0/9 (0%)	0	5/52 (9.6%)	5
BACTEREMIA, STAPHLOCOCCUS EPIDERMIS	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
Cardiac disorders
ACUTE CARDIAC ARREST DUE TO ARRYTHMIA	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
ACUTE CARDIOPULMONARY ARREST	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
ASYSTOLE	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
ATRIAL FIBRILLATION	0/9 (0%)	0	1/9 (11.1%)	1	1/52 (1.9%)	1
CARDIAC ARREST	0/9 (0%)	0	1/9 (11.1%)	1	2/52 (3.8%)	2
CARDIOGENIC SHOCK SECONDARY TO ATRIAL FIBRILLATION WITH RAPID VENTRICULAR RESPONSE	0/9 (0%)	0	1/9 (11.1%)	1	1/52 (1.9%)	1
CARDIOPULMONARY ARREST	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
CARDIOPULMONARY FAILURE	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
TACHYCARDIS	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
UNSTABLE ARRYTHMIA	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
Gastrointestinal disorders
GASTROINTESTINAL BLEED	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
Infections and infestations
METHYCILLIN-RESISTANT STAPHLOCOCCUS AUREUS BACTEREMIA	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
PROGRESSION OF COVID-19	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
SEPSIS	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
SEPTIC SHOCK	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
SEPTIC SHOCK SECONDARY TO METHICILLIN-SUSCEPTIBLE STAPHYLOCOCCUS AUREUS	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
SEVERE SEPSIS	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
Injury, poisoning and procedural complications
FALL	0/9 (0%)	0	1/9 (11.1%)	1	0/52 (0%)	0
Musculoskeletal and connective tissue disorders
CRITICAL ILLNESS MYOPATHY	1/9 (11.1%)	1	3/9 (33.3%)	3	6/52 (11.5%)	6
Nervous system disorders
ACUTE CEREBRAL EDEMA AND ACUTE ENCEPHALOPATHY RELATED TO SUBACUTE INFARCT	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
SEIZURE	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
SEVERE METABOLIC ENCEPHALOPATHY	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
TOXIC METABOLIC ENCEPHALOPATHY	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
TREMOR	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
Renal and urinary disorders
ACUTE RENAL FAILURE	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
OLIGOURIA	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
RENAL FAILURE	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE	0/9 (0%)	0	1/9 (11.1%)	1	3/52 (5.8%)	3
ASPIRATION PNEUMONITIS	0/9 (0%)	0	1/9 (11.1%)	1	0/52 (0%)	0
PNEUMONIA, EXTENDED-SPECTRUM BETA-LACTAMASE (ESBL) E COLI	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
PNEUMONIA	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
PULMONARY EMBOLISM	0/9 (0%)	0	0/9 (0%)	0	2/52 (3.8%)	2
PULMONARY EDEMA	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
RESPIRATORY FAILURE	0/9 (0%)	0	0/9 (0%)	0	10/52 (19.2%)	10
SHORTNESS OF BREATH	0/9 (0%)	0	1/9 (11.1%)	1	0/52 (0%)	0
TRACHEAL EDEMA	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
Vascular disorders
DEEP VEIN THROMBOSIS	0/9 (0%)	0	1/9 (11.1%)	1	0/52 (0%)	0
HEMATOMA	0/9 (0%)	0	0/9 (0%)	0	1/52 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Naltrexone		Ketamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		7/9 (77.8%)		52/52 (100%)
Blood and lymphatic system disorders
BLEEDING	0/9 (0%)	0	0/9 (0%)	0	10/52 (19.2%)	10
EPITAXIS	1/9 (11.1%)	1	0/9 (0%)	0	3/52 (5.8%)	3
THROMBOCYTOPENIA	1/9 (11.1%)	1	0/9 (0%)	0	3/52 (5.8%)	3
Cardiac disorders
ATRIAL FIBRILLATION WITH RAPID VENTRICULAR RATE	1/9 (11.1%)	1	0/9 (0%)	0	5/52 (9.6%)	5
CHEST PAIN	2/9 (22.2%)	2	0/9 (0%)	0	1/52 (1.9%)	1
ELEVATED HEART RATE/BLOOD PRESSURE	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
HYPOTENSION	1/9 (11.1%)	1	0/9 (0%)	0	3/52 (5.8%)	3
VENTRICULAR TACHYCARDIA	0/9 (0%)	0	0/9 (0%)	0	4/52 (7.7%)	4
Gastrointestinal disorders
EMESIS, ONE EPISODE	1/9 (11.1%)	1	0/9 (0%)	0	1/52 (1.9%)	1
EMESIS, FIVE EPISODES	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
MELENA	1/9 (11.1%)	1	1/9 (11.1%)	1	1/52 (1.9%)	1
General disorders
FEVER	1/9 (11.1%)	1	0/9 (0%)	0	3/52 (5.8%)	3
LETHARGY, INCREASED	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
XEROSTOMIA	0/9 (0%)	0	1/9 (11.1%)	1	0/52 (0%)	0
Injury, poisoning and procedural complications
FALL	2/9 (22.2%)	2	1/9 (11.1%)	1	0/52 (0%)	0
PAIN, WRIST	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
Musculoskeletal and connective tissue disorders
CRITICAL ILLNESS MYOPATHY	1/9 (11.1%)	1	0/9 (0%)	0	4/52 (7.7%)	4
Nervous system disorders
DIZZINESS	0/9 (0%)	0	1/9 (11.1%)	1	0/52 (0%)	0
HEADACHE	1/9 (11.1%)	1	0/9 (0%)	0	1/52 (1.9%)	1
TREMOR	0/9 (0%)	0	1/9 (11.1%)	1	1/52 (1.9%)	1
Psychiatric disorders
AGITATION	0/9 (0%)	0	0/9 (0%)	0	3/52 (5.8%)	3
ALTERED MENTAL STATUS	1/9 (11.1%)	1	0/9 (0%)	0	1/52 (1.9%)	1
Renal and urinary disorders
HEMATURIA	1/9 (11.1%)	1	0/9 (0%)	0	2/52 (3.8%)	2
URINARY RETENTION	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
Respiratory, thoracic and mediastinal disorders
HEMOPTYSIS	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
PULMONARY EMBOLISM	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
SHORTNESS OF BREATH	1/9 (11.1%)	1	0/9 (0%)	0	0/52 (0%)	0
Skin and subcutaneous tissue disorders
CYST, LOWER EXTREMITY	0/9 (0%)	0	1/9 (11.1%)	1	0/52 (0%)	0
DECUBITUS ULCER	0/9 (0%)	0	0/9 (0%)	0	3/52 (5.8%)	3
RASH	1/9 (11.1%)	1	0/9 (0%)	0	5/52 (9.6%)	5
Vascular disorders
DEEP VEIN THROMBOSIS	0/9 (0%)	0	1/9 (11.1%)	1	0/52 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.